Neurotransmitters
A.P.Dr. Raghad Emad Naji
Ph.D. Clinical biochemistry
Objectives
Define & classify neurotransmitters
Outline the transport & release of NT
Describe inactivation & reuptake of NT
Discuss the catecholamines, acetylcholine as an example
Definition
Neurotransmitters are the chemicals
which allow the transmission of
signals from one neuron to the next
across synapses. They are also found at
the axon endings of motor neurons,
where they stimulate the muscle fibers.
And they and their close relatives are
produced by some glands such as the
pituitary and the adrenal glands.
- Or they are substances that are produced by neurons, stored in the synapses,
and released into the synaptic cleft by exocytosis in response to a stimulus. At
the postsynaptic membrane, they bind to special receptors and affect their
activity.
The terminal button of the presynaptic neurons axon contains mitochondria
as well as microtubules that transport the neurotransmitters from the cell
body (where they are produced) to the tip of the axon.
The synaptic gap that the neurotransmitters have to cross is very narrowon
the order of 0.02 micron.
Across the gap, the
neurotransmitters bind to
membrane receptors( large
proteins anchored in the cell
membrane of the post-synaptic
neuron.)
- Each neuron usually releases only one type of
neurotransmitter. Neurons that release
dopamine are referred to as dopaminergic,, while
those that release acetylcholine are cholinergic,
- The transmitters that are released diffuse through the
synaptic cleft and bind on the other side to receptors on
the postsynaptic membrane.
Action
Neurons form elaborate networks through which nerve impulsesaction potentialstravel. Each
neuron has as many as 15,000 connections with neighboring neurons.
Neurons do not touch each other (except in the case of an electrical synapse through a gap
junction); instead, neurons interact at contact points called synapses: a junction within two nerve
cells, consisting of a miniature gap which impulses pass by a neurotransmitter. A neuron transports
its information by way of a nerve impulse called an action potential. When an action potential
arrives at the synapse's presynaptic terminal button, it may stimulate the release of
neurotransmitters. These neurotransmitters are released into the synaptic cleft to bind onto the
receptors of the postsynaptic membrane and influence another cell, either in an inhibitory or
excitatory way.
The next neuron may be connected to many more neurons, and if the total of excitatory influences
is greater than that of inhibitory influences, it will also "fire". That is to say, it will create a new
action potential at its axon hillock, releasing neurotransmitters and passing on the information to yet
another neighboring neuron.
Types of neurotransmitters
Amino acids: glutamate, aspartate, D-serine, γ-aminobutyric acid (GABA), glycine
Gasotransmitters: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H
2
S)
Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE,
NA), epinephrine (adrenaline), histamine, serotonin (SER, 5-HT)
Peptides: somatostatin, substance P, cocaine and amphetamine regulated
transcript, opioid peptides
Purines: adenosine triphosphate (ATP), adenosine
Others: acetylcholine (ACh)
β-endorphin is a relatively well-known example of a peptide neurotransmitter because it
engages in highly specific interactions with opioid receptors in the central nervous system.
Receptors :
Neurotransmitter receptors are protein complexes that span the cell membrane. Their nature determines
whether a given neurotransmitter is excitatory or inhibitory. Receptors that are continuously stimulated by
neurotransmitters or drugs become desensitized (downregulated); those that are not stimulated by their
neurotransmitter or are chronically blocked by drugs become supersensitive (upregulated). Downregulation or
upregulation of receptors strongly influences the development of tolerance and physical dependence.
One family of receptors, termed ionotropic receptors (eg, N-methyl-D-glutamate, nicotinic acetylcholine,
glycine, and γ-aminobutyric acid [GABA] receptors), consist of ion channels that open when bound to the
neurotransmitter and effect a very rapid response.
In the other family, termed metabotropic receptors (eg, serotonin, α- and β-adrenergic, and dopaminergic
receptors), neurotransmitters interact with G proteins and activate another molecule (2nd messenger such as
cAMP) that catalyzes a chain of events through protein phosphorylation or Ca mobilization, or both; cellular
changes mediated by 2nd messengers are slower and permit finer tuning of the rapid ionotropic
neurotransmitter response. Far more neurotransmitters activate specific receptors than 2nd messengers.
Catecholamines
Biosynthesis :
Dopamine, norepinephrine, and epinephrine (adrenalin) are biologically active
amines that are collectively termed catecholamines .Dopamine and norepinephrine
function as neurotransmitters in the brain and the autonomic nervous system.
Norepinephrine and epinephrine are also synthesized in the adrenal medulla.
The catecholamines are biogenic amines that have a catechol group. Their biosynthesis
in the adrenal cortex and CNS starts from tyrosine.
[1] Hydroxylation of the aromatic ring initially produces dopa. Dopa is also used in the treatment
of Parkinsons disease.
[2] Decarboxylation of dopa yields dopamine, an important transmitter in the CNS.
In dopaminergic neurons, catecholamine synthesis stops at this point.
[3] The adrenal gland and adrenergic neurons continue the synthesis by hydroxylating dopamine
into norepinephrine (noradrenaline).
Ascorbic acid (vitamin C) acts as a hydrogen-transferring coenzyme here.
[4] Finally, N-methylation of norepinephrine yields epinephrine (adrenaline). The coenzyme for
this reaction is S-adenosylmethionine .
Two catecholamines, norepinephrine and dopamine, act
as neuromodulators in the central nervous system and as hormones
in the blood circulation.
Catecholamines are produced mainly by the chromaffin cells of the adrenal
medulla and the postganglionic fibers of the sympathetic nervous
system. Dopamine, which acts as a neurotransmitter in the central nervous
system, is largely produced in neuronal cell bodies in two areas of the
brainstem: the ventral tegmental area and the substantia nigra.
The catecholamine norepinephrine is a neuromodulator of the peripheral
sympathetic nervous system but is also present in the blood (mostly through
"spillover" from the synapses of the sympathetic system).
Disorder :
High catecholamine levels in blood are associated with stress, which can be induced from psychological
reactions or environmental stressors such as elevated sound levels, intense light, or low blood sugar levels.
Extremely high levels of catecholamines (also known as catecholamine toxicity) can occur in central nervous
system trauma due to stimulation and/or damage of nuclei in the brainstem, in particular those nuclei affecting
the sympathetic nervous system. In emergency medicine, this occurrence is widely known as catecholamine
dump.
Extremely high levels of catecholamine can also be caused by neuroendocrine tumors in the adrenal medulla,
a treatable condition known as pheochromocytoma.
High levels of catecholamines can also be caused by monoamine oxidase A (MAO-A) deficiency. As MAO-A
is one of the enzymes responsible for degradation of these neurotransmitters, its deficiency increases the
bioavailability of these neurotransmitters considerably. It occurs in the absence of pheochromocytoma,
neuroendocrine tumors, and carcinoid syndrome, but it looks similar to carcinoid syndrome such as facial
flushing and aggression.
The acute porphyria's can cause elevated catecholamines.
Effects
Catecholamines cause general physiological changes that prepare the body
for physical activity (fight-or-flight response). Some typical effects are
increases in heart rate, blood pressure, blood glucose levels, and a general
reaction of the sympathetic nervous system. Some drugs, like tolcapone (a
central COMT-inhibitor), raise the levels of all the catecholamines.
Catecholamine is secreted into urine after being broken down, and its
secretion level can be measured for the diagnosis of illnesses associated with
catecholamine levels in the body. Urine testing for catecholamine is used to
detect pheochromocytoma.
Degradation of Catecholamines
The catecholamines are inactivated by oxidative deamination catalyzed by
monoamine oxidase (MAO), and by O-methylation carried out by catechole
O-methyl transferase (COMT).
The two reactions can occur in either order. The aldehyde products of the
MAO reaction are oxidized to the corresponding acids. The metabolic
products of these reactions are excreted in the urine as, and vanillyl mandelic
acid, metanephrine, and normetanephrine.
Monoamine Oxidase Inhibitors
MAO is found in neural and other tissues, such as the gut and liver.
In the neuron, this enzyme functions as a "safety valve" to oxidatively
deaminate and inactivate any excess neurotransmitter molecules
(norepinephrine, dopamine, or serotonin) that may leak out of synaptic
vesicles when the neuron is at rest. The MAO inhibitors
may irreversibly or
reversibly inactivate the enzyme, permitting neurotransmitter molecules to
escape degradation and, therefore, to both accumulate within the presynaptic
neuron and to leak into the synaptic space. This causes activation of
norepinephrine and serotonin receptors, and they are responsible for the
antidepressant action of these drugs.
Catechol-
O
-methyltransferase
COMT: is one of enzymes that degrade catecholamines such as
dopamine, epinephrine, and norepinephrine.
In humans, catechol-O-methyl transferase protein is encoded by the COMT
gene. As the regulation of catecholamines is impaired in a number of
medical conditions, several pharmaceutical drugs target COMT to alter its
activity and therefore the availability of catecholamines.
Acetylcholine
Acetylcholine : is synthesized from acetyl-CoA and choline in the cytoplasm of the
presynaptic axon and is stored in synaptic vesicles, each of which contains
around 100010 000 Cholinergic neurons are capable of producing ACh.
- ACh molecules, after it is released by exocytosis, the transmitter travels by
diffusion to the receptors on the postsynaptic membrane.
- The cleavage products choline and acetate are taken up again by the presynaptic
neuron and reused for acetylcholine synthesis.
- Substances that block the serine residue in the active center of
acetylcholinesterase.
The enzyme acetyl choline esterase converts acetylcholine into the inactive metabolites choline and acetate. This
enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is
essential for proper muscle function. Certain neurotoxins work by inhibiting acetylcholinesterase, thus leading to
excess acetylcholine at the neuromuscular junction, causing paralysis of the muscles needed for breathing and
stopping the beating of the heart.
In the brain, acetylcholine functions as a neurotransmitter and as a neuromodulator. The brain contains a number
of cholinergic areas, each with distinct functions. They play an important role in arousal, attention, memory and
motivation.
Partly because of its muscle-activating function, but also because of its functions in the autonomic nervous
system and brain, a large number of important drugs exert their effects by altering cholinergic transmission.
Numerous venoms and toxins produced by plants, animals, and bacteria, as well as chemical nerve agents such
as Sarin, cause harm by inactivating or hyperactivating muscles via their influences on the neuromuscular
junction. Drugs that act on muscarinic acetylcholine receptors, such as atropine, can be poisonous in large
quantities, but in smaller doses they are commonly used to treat certain heart conditions and eye problems.
The addictive qualities of nicotine derive from its effects on nicotinic acetylcholine receptors in the brain.
Function
Acetylcholine has functions both in the peripheral nervous system (PNS) and
in the central nervous system (CNS). In the peripheral nervous system,
acetylcholine activates muscles, and is a major neurotransmitter in the
autonomic nervous system. In the CNS, cholinergic projections from
the basal forebrain to the cerebral cortex and hippocampus support
the cognitive functions of those target areas.
Cellular effects
Acetylcholine processing in a synapse. After release acetylcholine is broken down by the
enzyme acetylcholinesterase.
Like many other biologically active substances, acetylcholine exerts its effects by binding to and
activating receptors located on the surface of cells.
There are two main classes of acetylcholine receptor, nicotinic and muscarinic. They are named for
chemicals that can selectively activate each type of receptor without activating the other: muscarine is a
compound found in the mushroom Amanita muscaria; nicotine is found in tobacco.
Nicotinic acetylcholine receptors are ligand-gated ion channels permeable to sodium, potassium,
and calcium ions. In other words, they are ion channels embedded in cell membranes, capable of
switching from a closed to open state when acetylcholine binds to them; in the open state they allow ions
to pass through.
Nicotinic receptors come in two main types, known as muscle-type and neuronal-type. The muscle-type
can be selectively blocked by curare, the neuronal-type by hexamethonium. The main location of muscle-
type receptors is on muscle cells.
Neuronal-type receptors are located in autonomic ganglia (both sympathetic and parasympathetic), and in
the central nervous system.
Direct Vascular Effects
Acetylcholine in the serum exerts a direct effect on vascular tone by binding
to muscarinic receptors present on vascular endothelium. These cells
respond by increasing production of nitric oxide, which signals the
surrounding smooth muscle to relax, leading to vasodilation
Neuromuscular junction:
Muscles contract when they receive signals from motor neurons. The neuromuscular junction is the site of
the signal exchange. The steps of this process in vertebrates occur as follows:
(1) The action potential reaches the axon terminal.
(2) Calcium ions flow into the axon terminal.
(3) Acetylcholine is released into the synaptic cleft.
(4) Acetylcholine binds to postsynaptic receptors.
(5) This binding causes ion channels to open and allows sodium ions to flow into the muscle cell.
(6) The flow of sodium ions across the membrane into the muscle cell generates an action potential which
induces muscle contraction.
The neurotoxins
(Organophosphates) prevent ACh degradation
and thus cause prolonged stimulation of the
postsynaptic cell.
- Curare, a paralyzing arrow-poison used by South
American Indians, competitively inhibits binding
of Ach to its receptor.
- Organic mercurial compounds, such
as methylmercury, have a high affinity
for sulfhydryl groups, which causes dysfunction
of the enzyme choline acetyltransferase. This
inhibition may lead to acetylcholine deficiency,
and can have consequences on motor function.
- Botulinum toxin (Botox) acts by suppressing
the release of acetylcholine